Heart failure is a common cardiovascular condition and has reached epidemic proportions in the United States and Europe (Remme et al., Eur. Heart J., 2001, vol. 22, pp. 1527-1560). The number of hospital admissions for acute heart failure is approaching 1 million each year in the United States alone. Currently, readmission rates and mortality have reached 30% to 40% within 60 days following discharge (Cuffee et al., JAMA, 2002, vol. 287(12), pp. 1541-7). In acute heart failure, worsening of hemodynamic function, in particular with very high left ventricular end-diastolic pressure is common.
The current treatment for acute heart failure is multifactorial and often differs among patients. While diuretics, vasodilators, and positive inotropes remain the mainstay in the treatment of patients with acute heart failure, these treatments are associated with mortality and high readmission rates.
Furthermore, existing inotropic therapies (eg, dobutamine) result in improved cardiac output, but with increased heart rate and increased myocardial oxygen consumption. These inotropic agents also carry with them a proarrhythmic potential in patients with heart failure. This cardiac liability is believed to be associated with the energy expense and calcium drive associated with these agents' direct positive inotropic actions.
In an effort to meet this growing unmet medical need, many new approaches have been studied with limited success in safely improving the hemodynamic status and outcome of patients with this syndrome. One such agent, the peptide human urocortin 2 (h-UCN2), has been studied in healthy subjects and patients with heart failure. This peptide was shown to increase left ventricular ejection fraction (LVEF) and cardiac output (CO) in a model of heart failure in sheep (Rademaker et al., Circulation, 2005, vol. 112, pp. 3624-3624). In subsequent intravenous infusion studies in 8 healthy subjects (Davis et al., J. Am. Coll. Cardiol., 2007, vol. 49, pp. 461-471) and in 8 subjects with heart failure (Davis et al., Eur. Heart J., 2007, vol. 28, pp. 2589-2597), the increases in LVEF and CO were accompanied by an increase in heart rate and decrease in blood pressure at both doses examined in each of the two studies. One-hour intravenous infusions of h-UCN2 in healthy subjects and patients appears to have been well tolerated.
Human stresscopin (h-SCP), a 40-amino-acid peptide, is related to h-UCN2 and both are members of the corticotrophin releasing hormone (CRH) peptide family. The biological actions of the CRH peptide family are elicited by two 7 transmembrane G-protein coupled receptors, CRH receptor type 1 (CRHR1) and CRH receptor type 2 (CRHR2). Although these receptors contain high sequence homology, the different members of the CRH peptide family express significant differences in their relative binding affinity, degree of receptor activation and selectivity for these two receptors.
Unlike many of the CRH family members, h-SCP expresses greater selectivity for the CRHR2 and acts as a mediator that aids in the process of attenuating the initiation and maintenance of physiological stress (Bale et al., Nat. Genet., 2000, vol. 24, pp. 410-414; Kishimoto et al., Nat. Genet., 2000, vol. 24, pp. 415-419). In addition to its apparent role in physiological stress, h-SCP has been reported to elicit a number of other physiological actions. It exerts effects on the endocrine (Li et al., Endocrinology, 2003, vol. 144, pp. 3216-3224), central nervous, cardiovascular (Bale et al., Proc. Natl. Acad. Sci., 2004, vol. 101, pp. 3697-3702; Tang et al., Eur. Heart J., 2007, vol. 28, pp. 2561-2562), pulmonary, gastrointestinal, renal, skeletal muscle, and inflammatory systems (Moffatt et al., FASEB J., 2006, vol. 20, pp. 1877-1879).
In addition, CRHR2 activity has been implicated in skeletal muscle wasting disease, such as sarcopenia (Hinkle et al., Endocrinology, 2003, vol. 144(11), pp. 4939-4946), motor activity and food intake (Ohata et al., Peptides, 2004, vol. 25, pp. 1703-1709), participates in a cardioprotective role (Brar et al., Endocrinology, 2004, vol. 145(1), pp. 24-35) and expresses bronchorelaxant and anti-inflammatory activity (Moffatt et al., FASEB J., 2006, vol. 20, pp. E1181-E1187).
Pegylation is a process of attaching one or more polyethylene glycol (PEG) polymers to molecules. Often, the process of pegylation is applied to antibodies, peptides and proteins to improve their biopharmaceutical properties and overcome a compound's susceptibility to proteolytic enzymes, short circulation half-life, short shelf live, low solubility, rapid renal clearance and the potential to generate antibodies to the administered drug (Harris et al., Nature, 2003, vol. 2, pp. 214-221; Hamidi et al., Drug Delivery, 2006, 3, pp. 399-409; Bailon et al., PSTT, 1998, vol. 1(8), pp. 352356). Recently, the FDA has approved PEG polymers for use as a vehicle or base in foods, cosmetics, and pharmaceuticals. Overall, PEG polymers are relatively non-immunogenic, have little toxicity, and are eliminated intact by the kidneys or in the feces. These features can result in a number of clinical benefits for the compound if this process is developed to preserve or improve the affinity, efficacy and pharmacologic profile of the parent molecule.